To explore the therapeutic effects of Nobiletin (NOB) on Idiopathic pulmonary fibrosis (IPF) and to identify its targets and molecular pathways. We verified the inhibitory effect of NOB on the senescence of A549 cells through in vitro experiments, and the inhibitory effect of NOB on the migration ability of fibroblasts was verified by the Transwell experiment. The inhibitory effects of NOB on Idiopathic IPF were subsequently assessed in a mouse model induced by bleomycin (BLM). Through PPI network, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, the PI3K/AKT/MDM2/p53 signaling pathway was identified as the critical pathway. The key proteins in the signaling pathway were verified by molecular docking and western blotting. NOB showed a great inhibitory effect on A549 cell senescence and Fibroblast migration. Meanwhile, NOB reduced BLM-induced collagen deposition in mouse lung tissues and inhibited alveolar epithelial cell (AEC) senescence. Through PPI network, P53 was screened as a core target of NOB. According to functional enrichment analysis results, the PI3K/AKT signaling was believed to have played an important role. Therefore, we speculate that the PI3K/AKT/MDM2/p53 signaling pathway mediated NOB’s impact on IPF. These findings were validated through molecular docking and western blotting. This study demonstrated that NOB suppressed cell senescence to protect IPF through mediating the PI3K/AKT/MDM2/p53 signaling pathway.
